This research focuses on the 7-transmembrane/G-protein coupled human thrombin receptor. Receptor activation precipitates complex signaling events culminating in platelet aggregation and cellular proliferation. One of the most potent stimuli of platelet aggregation is the blood clotting serine protease, alpha-thrombin. Alpha-thrombin exerts its action by recognizing andcleaving the N-terminal extracellular domain of a receptor located on the platelet membrane. Thethrombin receptor is thus activated by cleavage and subsequent exposure of a peptide figand tethered to the receptor itself, which obviates the need for high extracellular peptide hormone concentration. Once activated by alpha-thrombin, the receptor-intramolecular tethered ligand complex switches on a protein kinase cascade, Ca++ influx, and gene transcription. Current work addresses various aspects of receptor signaling including receptor down-regulation by secondary thrombin cleavage at specific sites within the thrombin extracellular domain. Mass spectrometry is used to identify reaction products generated by thrombin cleavage of a recombinant extracellular domain of thrombin (JR78). Insight into the molecular interactions between these thrombin receptor peptides and thrombin should provide leads for the development of anti-thrombotic agents.